Hot off the presses! Oct 28 Cell

The Oct 28 issue of the Cell is now up on Pubget (About Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• In This Issue
  - Cell 147(3):477,479 (2011)
  
• The Musicality of Franz Liszt
  - Cell 147(3):481,483 (2011)
  October marks the 200th birthday of the Hungarian musician Franz Liszt. Arguably one of the best pianists of all time, Liszt was renowned for his emotionally charged performances that sent waves of "Lisztomania" across Europe in the 1840s. But Liszt also composed ∼700 pieces, instructed >400 students, and pioneered new musical formats. In this Cell Culture, we follow a musical note through the mind of Liszt, from his outer hair cells and pitch-selective neurons to dopamine release at the climax of his Sonata in B minor.
• A Breath of Fresh Air in Lung Regeneration
  - Cell 147(3):485-487 (2011)
  Enhancing the ability of the lungs to regenerate following injury could revolutionize the treatment of a wide range of different diseases. In this issue, and dissect the cellular and molecular mechanisms of murine lung regeneration following injury and provide insights into the basic biology of the organ with implications for development of future therapeutic approaches.
• A Gutsy Way to Grow: Intestinal Stem Cells as Nutrient Sensors
  - Cell 147(3):487-489 (2011)
  Adult tissues can rapidly and reversibly change size to adapt to environmental and behavioral influences. In this issue, demonstrate that fly intestinal stem cells alter their division patterns in response to food availability to drive organ growth.
• You AhR What You Eat: Linking Diet and Immunity
  - Cell 147(3):489-491 (2011)
  The aryl hydrocarbon receptor (AhR) is responsible for the toxic effects of environmental pollutants such as dioxin, but little is known about its normal physiological functions. now show that specific dietary compounds present in cruciferous vegetables act through the AhR to promote intestinal immune function, revealing AhR as a critical link between diet and immunity.
• Dueling Ca2+ Sensors in Neurotransmitter Release
  - Cell 147(3):491-493 (2011)
  Ca2+-triggered neurotransmitter release is characterized by two kinetically distinct components: a fast synchronous phase and a slow asynchronous phase. now report that double C2 domain (Doc2) proteins function as high-affinity Ca2+ sensors to specifically regulate the asynchronous component of neurotransmitter release.
• Two Routes for Remembering the Past
  - Cell 147(3):493-495 (2011)
  Which brain circuits underlie retrieval of distant memories? use a powerful optogenetic-based approach to reveal the critical contribution of the hippocampus to remote memory retrieval. In so doing, they provide new evidence toward resolving a long-standing debate in cognitive neuroscience.
• Drop that Pipette: Science by Design
  - Cell 147(3):496-497 (2011)
  An unexpected collaboration between a synthetic biology lab at UCSF and a Palo Alto-based design firm is stirring up the way that research is conceived and conducted, by integrating innovation and "design thinking" into the scientific method.
• The Seeds of Neurodegeneration: Prion-like Spreading in ALS
  - Cell 147(3):498-508 (2011)
  Misfolded proteins accumulating in several neurodegenerative diseases (including Alzheimer, Parkinson, and Huntington diseases) can cause aggregation of their native counterparts through a mechanism similar to the infectious prion protein's induction of a pathogenic conformation onto its cellular isoform. Evidence for such a prion-like mechanism has now spread to the main misfolded proteins, SOD1 and TDP-43, implicated in amyotrophic lateral sclerosis (ALS). The major neurodegenerative diseases may therefore have mechanistic parallels for non-cell-autonomous spread of disease within the nervous system.
• Molecular Mechanisms of Fear Learning and Memory
  - Cell 147(3):509-524 (2011)
  Pavlovian fear conditioning is a particularly useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here, we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear condition! ing. Collectively, this body of research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals and potentially for understanding fear-related disorders, such as PTSD and phobias.
• Distal Airway Stem Cells Yield Alveoli In Vitro and during Lung Regeneration following H1N1 Influenza Infection
  - Cell 147(3):525-538 (2011)
  The extent of lung regeneration following catastrophic damage and the potential role of adult stem cells in such a process remains obscure. Sublethal infection of mice with an H1N1 influenza virus related to that of the 1918 pandemic triggers massive airway damage followed by apparent regeneration. We show here that p63-expressing stem cells in the bronchiolar epithelium undergo rapid proliferation after infection and radiate to interbronchiolar regions of alveolar ablation. Once there, these cells assemble into discrete, Krt5+ pods and initiate expression of markers typical of alveoli. Gene expression profiles of these pods suggest that they are intermediates in the reconstitution of the alveolar-capillary network eradicated by viral infection. The dynamics of this p63-expressing stem cell in lung regeneration mirrors our parallel finding that defined pedigrees of human distal airway stem cells assemble alveoli-like structures in vitro and suggests new therapeutic ave! nues to acute and chronic airway disease.
• Endothelial-Derived Angiocrine Signals Induce and Sustain Regenerative Lung Alveolarization
  - Cell 147(3):539-553 (2011)
  To identify pathways involved in adult lung regeneration, we employ a unilateral pneumonectomy (PNX) model that promotes regenerative alveolarization in the remaining intact lung. We show that PNX stimulates pulmonary capillary endothelial cells (PCECs) to produce angiocrine growth factors that induce proliferation of epithelial progenitor cells supporting alveologenesis. Endothelial cells trigger expansion of cocultured epithelial cells, forming three-dimensional angiospheres reminiscent of alveolar-capillary sacs. After PNX, endothelial-specific inducible genetic ablation of Vegfr2 and Fgfr1 in mice inhibits production of MMP14, impairing alveolarization. MMP14 promotes expansion of epithelial progenitor cells by unmasking cryptic EGF-like ectodomains that activate the EGF receptor (EGFR). Consistent with this, neutralization of MMP14 impairs EGFR-mediated alveolar regeneration, whereas administration of EGF or intravascular transplantation of MMP14+ PCECs into pneum! onectomized Vegfr2/Fgfr1-deficient mice restores alveologenesis and lung inspiratory volume and compliance function. VEGFR2 and FGFR1 activation in PCECs therefore increases MMP14-dependent bioavailability of EGFR ligands to initiate and sustain alveologenesis.
• The Eph-Receptor A7 Is a Soluble Tumor Suppressor for Follicular Lymphoma
  - Cell 147(3):554-564 (2011)
  Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 (EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7TR) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7TR protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7TR to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7TR as tumor suppressor wi! th immediate therapeutic potential.
• Master Transcription Factors Determine Cell-Type-Specific Responses to TGF-β Signaling
  - Cell 147(3):565-576 (2011)
  Transforming growth factor beta (TGF-β) signaling, mediated through the transcription factors Smad2 and Smad3 (Smad2/3), directs different responses in different cell types. Here we report that Smad3 co-occupies the genome with cell-type-specific master transcription factors. Thus, Smad3 occupies the genome with Oct4 in embryonic stem cells (ESCs), Myod1 in myotubes, and PU.1 in pro-B cells. We find that these master transcription factors are required for Smad3 occupancy and that TGF-β signaling largely affects the genes bound by the master transcription factors. Furthermore, we show that induction of Myod1 in nonmuscle cells is sufficient to redirect Smad3 to Myod1 sites. We conclude that cell-type-specific master transcription factors determine the genes bound by Smad2/3 and are thus responsible for orchestrating the cell-type-specific effects of TGF-β signaling.
• Lineage Regulators Direct BMP and Wnt Pathways to Cell-Specific Programs during Differentiation and Regeneration
  - Cell 147(3):577-589 (2011)
  BMP and Wnt signaling pathways control essential cellular responses through activation of the transcription factors SMAD (BMP) and TCF (Wnt). Here, we show that regeneration of hematopoietic lineages following acute injury depends on the activation of each of these signaling pathways to induce expression of key blood genes. Both SMAD1 and TCF7L2 co-occupy sites with master regulators adjacent to hematopoietic genes. In addition, both SMAD1 and TCF7L2 follow the binding of the predominant lineage regulator during differentiation from multipotent hematopoietic progenitor cells to erythroid cells. Furthermore, induction of the myeloid lineage regulator C/EBPα in erythroid cells shifts binding of SMAD1 to sites newly occupied by C/EBPα, whereas expression of the erythroid regulator GATA1 directs SMAD1 loss on nonerythroid targets. We conclude that the regenerative response mediated by BMP and Wnt signaling pathways is coupled with the lineage master regulators to control! the gene programs defining cellular identity.
• Molecular Architecture of the Transport Channel of the Nuclear Pore Complex
  - Cell 147(3):590-602 (2011)
  The nuclear pore complex encloses a central channel for nucleocytoplasmic transport, which is thought to consist of three nucleoporins, Nup54, Nup58, and Nup62. However, the structure and composition of the channel are elusive. We determined the crystal structures of the interacting domains between these nucleoporins and pieced together the molecular architecture of the mammalian transport channel. Located in the channel midplane is a flexible Nup54⋅Nup58 ring that can undergo large rearrangements yielding diameter changes from ∼20 to ∼40 nm. Nup62⋅Nup54 triple helices project alternately up and down from either side of the midplane ring and form nucleoplasmic and cytoplasmic entries. The channel consists of as many as 224 copies of the three nucleoporins, amounting to a molar mass of 12.3 MDa and contributing 256 phenylalanine-glycine repeat regions. We propose that the occupancy of these repeat regions with transport receptors modulates ring diameter and tran! sport activity.
• Altered Modes of Stem Cell Division Drive Adaptive Intestinal Growth
  - Cell 147(3):603-614 (2011)
  Throughout life, adult organs continually adapt to variable environmental factors. Adaptive mechanisms must fundamentally differ from homeostatic maintenance, but little is known about how physiological factors elicit tissue remodeling. Here, we show that specialized stem cell responses underlie the adaptive resizing of a mature organ. In the adult Drosophila midgut, intestinal stem cells interpret a nutrient cue to "break homeostasis" and drive growth when food is abundant. Activated in part by niche production of insulin, stem cells direct a growth program through two altered modes of behavior: accelerated division rates and predominance of symmetric division fates. Together, these altered modes produce a net increase in total intestinal cells, which is reversed upon withdrawal of food. Thus, tissue renewal programs are not committed to maintain cellular equilibrium; stem cells can remodel organs in response to physiological triggers.
• Arc/Arg3.1 Regulates an Endosomal Pathway Essential for Activity-Dependent β-Amyloid Generation
  - Cell 147(3):615-628 (2011)
  Assemblies of β-amyloid (Aβ) peptides are pathological mediators of Alzheimer's Disease (AD) and are produced by the sequential cleavages of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. The generation of Aβ is coupled to neuronal activity, but the molecular basis is unknown. Here, we report that the immediate early gene Arc is required for activity-dependent generation of Aβ. Arc is a postsynaptic protein that recruits endophilin2/3 and dynamin to early/recycling endosomes that traffic AMPA receptors to reduce synaptic strength in both Hebbian and non-Hebbian forms of plasticity. The Arc-endosome also traffics APP and BACE1, and Arc physically associates with presenilin1 (PS1) to regulate γ-secretase trafficking and confer activity dependence. Genetic deletion of Arc reduces Aβ load in a transgenic mouse model of AD. In concert with the finding that patients with AD can express anomalously high levels of Arc, we hypoth! esize that Arc participates in the pathogenesis of AD.
• Exogenous Stimuli Maintain Intraepithelial Lymphocytes via Aryl Hydrocarbon Receptor Activation
  - Cell 147(3):629-640 (2011)
  The body's surfaces form the interface with the external environment, protecting the host. These epithelial barriers are also colonized by a controlled diversity of microorganisms, disturbances of which can give rise to disease. Specialized intraepithelial lymphocytes (IELs), which reside at these sites, are important as a first line of defense as well as in epithelial barrier organization and wound repair. We show here that the aryl hydrocarbon receptor (AhR) is a crucial regulator in maintaining IEL numbers in both the skin and the intestine. In the intestine, AhR deficiency or the lack of AhR ligands compromises the maintenance of IELs and the control of the microbial load and composition, resulting in heightened immune activation and increased vulnerability to epithelial damage. AhR activity can be regulated by dietary components, such as those present in cruciferous vegetables, providing a mechanistic link between dietary compounds, the intestinal immune system, a! nd the microbiota. PaperFlick View Within Article
• Motor Neuron Position and Topographic Order Imposed by β- and γ-Catenin Activities
  - Cell 147(3):641-652 (2011)
  Neurons typically settle at positions that match the location of their synaptic targets, creating topographic maps. In the spinal cord, the organization of motor neurons into discrete clusters is linked to the location of their muscle targets, establishing a topographic map of punctate design. To define the significance of motor pool organization for neuromuscular map formation, we assessed the role of cadherin-catenin signaling in motor neuron positioning and limb muscle innervation. We find that joint inactivation of β- and γ-catenin scrambles motor neuron settling position in the spinal cord but fails to erode the predictive link between motor neuron transcriptional identity and muscle target. Inactivation of N-cadherin perturbs pool positioning in similar ways, albeit with reduced penetrance. These findings reveal that cadherin-catenin signaling directs motor pool patterning and imposes topographic order on an underlying identity-based neural map. PaperClip View Within Article
• Patterns of Spinal Sensory-Motor Connectivity Prescribed by a Dorsoventral Positional Template
  - Cell 147(3):653-665 (2011)
  Sensory-motor circuits in the spinal cord are constructed with a fine specificity that coordinates motor behavior, but the mechanisms that direct sensory connections with their motor neuron partners remain unclear. The dorsoventral settling position of motor pools in the spinal cord is known to match the distal-to-proximal position of their muscle targets in the limb, but the significance of invariant motor neuron positioning is unknown. An analysis of sensory-motor connectivity patterns in FoxP1 mutant mice, where motor neuron position has been scrambled, shows that the final pattern of sensory-motor connections is initiated by the projection of sensory axons to discrete dorsoventral domains of the spinal cord without regard for motor neuron subtype or, indeed, the presence of motor neurons. By implication, the clustering and dorsoventral settling position of motor neuron pools serve as a determinant of the pattern of sensory input specificity and thus motor coordinat! ion. PaperClip View Within Article
• Doc2 Is a Ca2+ Sensor Required for Asynchronous Neurotransmitter Release
  - Cell 147(3):666-677 (2011)
  Synaptic transmission involves a fast synchronous phase and a slower asynchronous phase of neurotransmitter release that are regulated by distinct Ca2+ sensors. Though the Ca2+ sensor for rapid exocytosis, synaptotagmin I, has been studied in depth, the sensor for asynchronous release remains unknown. In a screen for neuronal Ca2+ sensors that respond to changes in [Ca2+] with markedly slower kinetics than synaptotagmin I, we observed that Doc2—another Ca2+, SNARE, and lipid-binding protein—operates on timescales consistent with asynchronous release. Moreover, up- and downregulation of Doc2 expression levels in hippocampal neurons increased or decreased, respectively, the slow phase of synaptic transmission. Synchronous release, when triggered by single action potentials, was unaffected by manipulation of Doc2 but was enhanced during repetitive stimulation in Doc2 knockdown neurons, potentially due to greater vesicle availability. In summary, we propose that Doc2 i! s a Ca2+ sensor that is kinetically tuned to regulate asynchronous neurotransmitter release.
• Dynamics of Retrieval Strategies for Remote Memories
  - Cell 147(3):678-689 (2011)
  Prevailing theory suggests that long-term memories are encoded via a two-phase process requiring early involvement of the hippocampus followed by the neocortex. Contextual fear memories in rodents rely on the hippocampus immediately following training but are unaffected by hippocampal lesions or pharmacological inhibition weeks later. With fast optogenetic methods, we examine the real-time contribution of hippocampal CA1 excitatory neurons to remote memory and find that contextual fear memory recall, even weeks after training, can be reversibly abolished by temporally precise optogenetic inhibition of CA1. When this inhibition is extended to match the typical time course of pharmacological inhibition, remote hippocampus dependence converts to hippocampus independence, suggesting that long-term memory retrieval normally depends on the hippocampus but can adaptively shift to alternate structures. Further revealing the plasticity of mechanisms required for memory recall, ! we confirm the remote-timescale importance of the anterior cingulate cortex (ACC) and implicate CA1 in ACC recruitment for remote recall.
• A Protein Complex Network of Drosophila melanogaster
  - Cell 147(3):690-703 (2011)
  Determining the composition of protein complexes is an essential step toward understanding the cell as an integrated system. Using coaffinity purification coupled to mass spectrometry analysis, we examined protein associations involving nearly 5,000 individual, FLAG-HA epitope-tagged Drosophila proteins. Stringent analysis of these data, based on a statistical framework designed to define individual protein-protein interactions, led to the generation of a Drosophila protein interaction map (DPiM) encompassing 556 protein complexes. The high quality of the DPiM and its usefulness as a paradigm for metazoan proteomes are apparent from the recovery of many known complexes, significant enrichment for shared functional attributes, and validation in human cells. The DPiM defines potential novel members for several important protein complexes and assigns functional links to 586 protein-coding genes lacking previous experimental annotation. The DPiM represents, to our knowledg! e, the largest metazoan protein complex map and provides a valuable resource for analysis of protein complex evolution.
• A Mechanism for Tunable Autoinhibition in the Structure of a Human Ca2+/Calmodulin- Dependent Kinase II Holoenzyme
  - Cell 147(3):704 (2011)
  
• SnapShot: Autism and the Synapse
  - Cell 147(3):706-706.e1 (2011)